Prediction of drug distribution in vivo on the basis of in vitro binding data

162

183

ABSTRACT:Currently used methodology for determining unbound drug exposure in brain combines measurement of the total drug concentration in the whole brain in vivo with estimation of brain tissue binding from one of two available in vitro methods: equilibrium dialysis of brain homogenate and the brain slice uptake method. This study of 56 compounds compares the fraction of unbound drug in brain (f u,brain ), determined using the brain homogenate method, with the unbound volume of distribution in brain (V u,brain ), determined using the brain slice method. Discrepancies were frequent and were primarily related to drug pH partitioning, attributable to the preservation of cellular structures in the slice that are absent in the homogenate. A mathematical model for pH partitioning into acidic intracellular compartments was derived to predict the slice V u,brain from measurements of f u,brain and drug pK a .This model allowed prediction of V u,brain from f u,brain within a 2.2-fold error range for 95% of the drugs compared with a 4.5-fold error range using the brain homogenate f u,brain method alone. The greatest discrepancies between the methods occurred with compounds that are actively transported into brain cells, including gabapentin, metformin, and prototypic organic cation transporter substrates. It was concluded that intrabrain drug distribution is governed by several diverse mechanisms in addition to nonspecific binding and that the slice method is therefore more reliable than the homogenate method. As an alternative, predictions of V u,brain can be made from homogenate f u,brain using the pH partition model presented, although this model does not take into consideration possible active brain cell uptake.

Section: Comparison Of Brain Slice and Brain Homogenate Methodsmentioning

confidence: 99%

Measurement of Unbound Drug Exposure in Brain: Modeling of pH Partitioning Explains Diverging Results between the Brain Slice and Brain Homogenate Methods

Fridén

Bergström²,

Wan³

et al. 2010

162

183

“…More recently, an approach to estimate brain penetration of drugs using binding experiments conducted with homogenates of brain tissue has been described previously (Kalvass et al, 2007). Furthermore, historically, some comparative studies have been conducted on the properties of drug binding to tissues (Kurz and Fichtl, 1983;Schuhmann et al, 1987;Clausen and Bickel, 1993;Ballard et al, 2003). However, a study on the ability to use in vitro tissue-binding experiments to quantitatively predict the V ss of a wide range of drugs has not been conducted.…”

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confidence: 99%

Prediction of V_ss from In Vitro Tissue-Binding Studies

Berry¹,

Roberts²,

Be³

et al. 2009

ABSTRACT:To predict volume of distribution at steady-state (V ss ), empirical (e.g., allometry) and mechanistic (using physicochemical property data and plasma protein binding) methods have been used. None of these approaches has been able to predict V ss accurately for the total compliment of a wide range of drugs. Therefore, alternative approaches would be of value. This study evaluates the utility of in vitro nonspecific tissue-binding measurements in predicting V ss for a wide range of drugs in rats. Literature as well as proprietary compounds were studied. It was found that in vitro tissue-binding measurements combined with calculated effects of the pH partition hypothesis often predict V ss more accurately than other available mechanistic methods and that this approach can compliment existing methods. The V ss values for some compounds were not accurately predicted using either nonspecific tissue-binding experiments or other available mechanistic methods. The V ss for these drugs may not be describable by nonspecific tissue binding alone; there may be significant specific components to the mechanism of distribution for these drugs, such as pH-dependent uptake into lysosomes (primarily strongly basic drugs), active transport, and/or enterohepatic recirculation. A lack of prediction for certain drugs warrants further investigation into these mechanisms and their application to more accurate prediction of V ss by mechanistic means.The apparent volume of distribution at steady state (V ss ) is one of the primary descriptive terms derived from pharmacokinetic (PK) analysis of the concentration-time profile after intravenous administration of drugs.

“…Following this expectation, attempts have been made to predict tissue partitioning from in vitro estimates of unbound plasma fraction and unbound tissue fraction with mixed success (Bickel and Gerny, 1980;Bickel et al, 1987;Schuhmann et al, 1987;Clausen and Bickel, 1993). Previous reports suggest that the dilution, homogenization, and incubation process necessary to determine unbound tissue fraction by equilibrium dialysis may disrupt or destroy intracellular components that contribute to distribution in vivo.…”

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confidence: 99%

Relationship Between Exposure and Nonspecific Binding of Thirty-Three Central Nervous System Drugs in Mice

Maurer

DeBartolo²,

Tess³

et al. 2004

207

171

ABSTRACT:Unbound fractions in mouse brain and plasma were determined for 31 structurally diverse central nervous system (CNS) drugs and two active metabolites. Three comparisons were made between in vitro binding and in vivo exposure data, namely: 1) mouse brainto-plasma exposure versus unbound plasma-to-unbound brain fraction ratio (fu plasma /fu brain ), 2) cerebrospinal fluid-to-brain exposure versus unbound brain fraction (fu brain ), and 3) cerebrospinal fluid-to-plasma exposure versus unbound plasma fraction (fu plasma ). Unbound fraction data were within 3-fold of in vivo exposure ratios for the majority of the drugs examined (i.e., 22 of 33), indicating a predominately free equilibrium across the blood-brain and blood-CSF barriers. Some degree of distributional impairment at either the blood-CSF or the blood-brain barrier was indicated for 8 of the 11 remaining drugs (i.e., carbamazepine, midazolam, phenytoin, sulpiride, thiopental, risperidone, 9-hydroxyrisperidone, and zolpidem). In several cases, the indicated distributional impairment is consistent with other independent literature reports for these drugs. Through the use of this approach, it appears that most CNS-active agents freely equilibrate across the blood-brain and blood-CSF barriers such that unbound drug concentrations in brain approximate those in the plasma. However, these results also support the intuitive concept that distributional impairment does not necessarily preclude CNS activity.